While it is known that some degree of protective immunity develops during the course of syphilitic infection, there is a paucity of information regarding the mechanism(s) involved and consequently an ambiguity in the criteria required to assess the efficiency of the immune process. CDC have recently reported a substantial increase in incidence of primary and secondary syphilis particularly among women of childbearing age and consequently an unacceptable increase in congenital syphilis. This, together with recent reports of exacerbation of the disease in patients with the HIV virus infection, justify the concern of Public Health officials and researchers alike in the search for mechanisms contributing to the process of immunity in syphilis. Our previous studies have indicated that the immunology of T. pallidum infection in susceptible guinea pigs mimics critical aspects of human syphilis (wide spectrum of treponemal antibodies, production of circulating immune complexes, and autoantibodies to host antigens), and a delayed resistance to reinfection. We have also provided evidence for an important role of cell-mediated immunity (CMI) in protection against challenge with T. pallidum. In this proposal and as a continuation of our previous studies, we have designed experiments to explore the role of pathogen-specific and cross-reacting antibodies alone or in combination with CMI in the process of resistance to syphilitic infection. We propose also, to further delineate both humoral and cellular mechanisms with the potential capability of preventing or promoting the immune process during the course of infection. For these studies guinea pigs of inbred strain 2 will be used. The background information required to execute the proposed experiments has been obtained during our previous studies with this experimental model. With the increasing interest in recombinant treponemal antigens, one can also see the need for an adequate experimental model (readily available inbred strain) to examine the role of specific epitopes in the expression of the immune response and to explore the ways in which the cellular and humoral defenses recognize these epitopes in vivo.